1. Field of the Invention
The present invention relates to new camptothecin derivatives useful as anti-tumor agents or intermediates thereof and to a process for preparing such derivatives. More particularly, the present invention relates to new prodrug-type camptothecin derivatives which exhibit excellent anti-tumor activity in living body with a low level of toxicity as well as a process for the preparation of the new camptothecin derivatives starting from 7-ethylcamptothecin.
2. Description of the Prior Art
Camptothecin is an alkaloid extracted and isolated from Camptotheca acuminata (Nyssaceae), etc., which has a pentacyclic structure consisting of a characteristic fused 5-ring system consisting of quinoline (rings A and B), pyrroline (ring C), .alpha.-pyridone (ring D) and a six-membered lactone (ring E) and is distinguished by displaying a strong inhibitory activity toward biosynthesis of nucleic acid. In addition, camptothecin is a unique anti-tumor substance characterized by its rapid and reversible action and its lack of any cross-tolerance with the existing anti-tumor agents and by exhibiting a strong anti-tumor activity against experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 sarcoma in rats. Although camptothecin is still regarded as one of the most potent substances possessing anti-tumor activity, the use of this compound itself for clinical treatments is significantly limited because of its high toxicity. Moreover, camptothecin and the majority of derivatives thereof are sparingly soluble in water and thus involve a problem in case of administration as medicaments.
Accordingly, a number of attempts have been made not only to reduce toxicity of camptothecin while maintaining its anti-tumor activity by converting camptothecin chemically into its derivatives but also to make camptothecin and derivatives thereof easily soluble in water by chemical modifications of the camptothecin molecule or substituents therein. As one of such attempts, 10-hydroxy-substituted derivatives among the camptothecin derivatives having been prepared hitherto provided interesting results in that the 10-hydroxy-substituted derivatives maintain an excellent anti-tumor activity with reduced toxicity. However, the derivatives were found to be sparingly soluble in water and therefore cannot be used as a medicament without difficulty. As a method for making camptothecin derivatives soluble in water, for example, a ring-opening reaction for the E-ring (lactone ring) of the camptothecin derivatives was used in the prior arts to form an alkali metal salt of the carboxyl function. However, a result of any chemical modification of the ring E, including such ring-opening reaction, revealed only failure in maintaining anti-tumor activity and very poor improvement in toxicity [J. Med. Chem., 19 (1976), 675].
According to a prior report, a water-soluble derivative of camptothecin of the formula (II) (hereinafter referred to as camptothecin sodium salt) obtainable by the treatment of the E-ring (the lactone moiety) of camptothecin with an aqueous sodium hydroxide solution is not found to be useful as anti-tumor agent because of its toxicity of causing e.g. myelosuppression or hemorrhagic cystitis constituting a dose limiting factor [Cancer Chemother. Rep., 54, 461 (1970)]. ##STR2## M. C. Wani et al, reported that the anti-tumor activity of the camptothecin sodium salt is reduced to a fraction of what is found in a derivative with the lactone form [M. C. Wani et al., J. Med. Chem., 23, 554 (1980)]. It has been believed since then that the E-ring (the lactone moiety) of camptothecin, including the 20-hydroxyl group, is an essential partial structure for camptothecin to exhibit its anti-tumor activity. Any of the few previous reports on the chemical modification of the E-ring (the lactone moiety) revealed that the derivatives obtained by such chemical modification exhibit only a little or no anti-tumor activity. For example, an E-ring (lactone)-opened derivative as the methylamide of the formula (III) shown below or as the isopropylamide of the formula (IV) shown below was reported to show a very little or no activity [The Alkaloids, ed. by A. Brossi, Academic Press, N.Y., 1983 and J. Med. Chem., 22, 310 (1979)]. ##STR3##
(wherein R is H, acetyl or propionyl.)
From the studies on various camptothecin derivatives prepared heretofore, it now becomes evident that chemical modifications in the E-ring, especially the E-ring opening of camptothecin derivatives significantly adversely affect the anti-tumor activity. Under the circumstances, there is a great demand in this art for developing a new class of camptothecin derivatives maintaining strong anti-tumor activity even if chemically modified in the E-ring.
As a part of our studies on the preparation of water-soluble prodrug-type derivatives of camptothecin, we fixed our eyes on the E-ring of camptothecin derivatives to explore the possibility of converting them into a prodrug form. As the 17-hydroxy group of camptothecin in free form is spontaneously cyclized under a neutral condition with the partner carboxyl group to form a lactone ring, we have made extensive researches to solve simultaneously both problems of making the derivatives water-soluble and reconstructing the E-ring of the E-ring-opened derivatives in living body after administration by masking the 17-hydroxy group of the E-ring-opened derivatives with such a protecting group as will be split off by hydrolysis by the action of an endogenous enzyme and converting the partner carboxyl group into a water-soluble carboxamide group.